AML is a highly lethal hematologic malignancy responsible for approximately 9000 deaths annually in the US. Therapy for the disease has not changed substantially in several decades, despite extensive clinical trials of cytotoxic chemotherapy. Thus, novel therapeutic approaches are necessary. Investigators at the University of Pennsylvania have demonstrated activation of the PI3 kinase pathway in nearly all primary AML samples and activation of this pathway is necessary for AML cell survival. Inhibition of PI3K's downstream effector, mammalian target of rapamycin (mTOR), using the clinically available reagent rapamycin dramatically enhances chemosensitivity of AML blasts and AML stem cells in preclinical models yet has minimal toxicity to normal marrow elements. We therefore completed a Phase I clinical trial demonstrating that safety of rapamycin and etoposide-based chemotherapy in relapsed/refractory AML. However, this trial was neither successful in validating target inhibition nor did it demonstrate an obvious advantage of the combination regimen in remission induction. To refine our approach, we performed a subsequent pilot study in which we tested a novel schedule of rapamycin and chemotherapy and I optimized a novel flow cytometric application to provide pharmacodynamic monitoring of mTOR inhibition in AML blasts. This demonstrated conclusive target inhibition during therapy and suggested that rapamycin improved chemotherapy response rate. Based upon these data, we propose in this application to: 1) Perform a Phase II clinical trial of rapamycin plus chemotherapy and establish a preliminary estimate of efficacy of the regimen's efficacy, 2) Perform pharmacodynamic analysis of samples from patients on this trial in order to determine if rapamycin inhibits mTOR signaling in leukemia cells, and 3) Study mechanisms of resistance to rapamycins using samples from the clinical trial and laboratory based approaches. Successful completion of this 5-year research plan will serve as practical and formal training and help establish my career as a translational researcher investigating the integration of signal transduction inhibitors into clinical therapeutics for AML.